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The Differential Immune Responses to COVID-19 in Peripheral and Lung

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The Differential Immune Responses to COVID-19 in Peripheral and Lung Xu et al. Cell Discovery (2020) 6:73 Cell Discovery https://doi.org/10.1038/s41421-020-00225-2 www.nature.com/celldisc ARTICLE Open Access The differential immune responses to COVID-19 in peripheral and lung revealed by single-cell RNA sequencing Gang Xu1,FurongQi1, Hanjie Li2, Qianting Yang1, Haiyan Wang1,XinWang1, Xiaoju Liu3, Juanjuan Zhao1, Xuejiao Liao1, Yang Liu1,LeiLiu1,ShuyeZhang 4 and Zheng Zhang 1 Abstract Understanding the mechanism that leads to immune dysfunction in severe coronavirus disease 2019 (COVID-19) is crucial for the development of effective treatment. Here, using single-cell RNA sequencing, we characterized the peripheral blood mononuclear cells (PBMCs) from uninfected controls and COVID-19 patients and cells in paired broncho-alveolar lavage fluid (BALF). We found a close association of decreased dendritic cells (DCs) and increased monocytes resembling myeloid-derived suppressor cells (MDSCs), which correlated with lymphopenia and inflammation in the blood of severe COVID-19 patients. Those MDSC-like monocytes were immune-paralyzed. In contrast, monocyte-macrophages in BALFs of COVID-19 patients produced massive amounts of cytokines and chemokines, but secreted little interferons. The frequencies of peripheral T cells and NK cells were significantly decreased in severe COVID-19 patients, especially for innate-like T and various CD8+ T cell subsets, compared to healthy controls. In contrast, the proportions of various activated CD4+ T cell subsets among the T cell compartment, including Th1, Th2, and Th17-like cells were increased and more clonally expanded in severe COVID-19 patients. ’ 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Patients peripheral T cells showed no sign of exhaustion or augmented cell death, whereas T cells in BALFs produced higher levels of IFNG, TNF, CCL4, CCL5, etc. Paired TCR tracking indicated abundant recruitment of peripheral T cells to the severe patients’ lung. Together, this study comprehensively depicts how the immune cell landscape is perturbed in severe COVID-19. Introduction cases have asymptomatic or mild-to-moderate diseases, Coronavirus disease 2019 (COVID-19) caused by severe around 10% of those infected may develop severe pneu- acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monia and other associated organ malfunctions1. Old age, has been spreading rapidly worldwide, causing serious male sex, and underlying comorbidities are risk factors for public health crisis. Although most SARS-CoV-2-infected causing severe COVID-192; however, the pathogenesis mechanisms remains unclear. Immune perturbations were thought to play crucial roles in the COVID-19 Correspondence: Lei Liu ([email protected])or pathogenesis. Indeed, many reports showed that lym- Shuye Zhang ([email protected])or Zheng Zhang ([email protected]) phopenia and increased blood cytokine levels were closely 1Institute for Hepatology, National Clinical Research Center for Infectious associated with the development or recovery of severe ’ fi Disease, Shenzhen Third People s Hospital, The Second Af liated Hospital, COVID-19 and proposed to treat the patients by inhi- School of Medicine, Southern University of Science and Technology, Shenzhen, 3–6 Guangdong 518112, China biting cytokine storms . 2CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute Recent studies have revealed more aspects of different of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese immune players in COVID-19 infections. Although Academy of Sciences, Shenzhen, Guangdong 518055, China Full list of author information is available at the end of the article SARS-CoV-2 infection in host cells elicits robust secretion These authors contributed equally: Gang Xu, Furong Qi, Hanjie Li © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Xu et al. Cell Discovery (2020) 6:73 Page 2 of 14 of chemokines and cytokines, it only weakly produces The clustering analysis showed 29 clusters and 10 major interferons (IFNs)7. In our earlier studies, we showed cell types annotated by marker genes, including T cell + increased recruitment of highly inflammatory FCN1 (CD3D), NK cell (KLRF1), B cell (CD79A), monocyte monocyte-derived macrophages in patients’ broncho- (CD14, FCGR3A), myeloid DCs (mDCs) (CD1C), plas- alveolar lavage fluids (BALFs), suggesting their implica- macytoid DCs (pDCs) (IL3RA), and plasma cells (PCs) tion in the cytokine storm8,9. Intriguingly, T and B cell (IGKC), megakaryocyte (MYL9), cycling cells (MKI67), responses and neutralizing antibodies recognizing SARS- and erythrocyte (HBB) (Fig. 1b, c and Supplementary Fig. CoV-2 were detected among most of the infected patients, S1a, b). By visual inspection, the data integration was with higher levels in those with old age and severe dis- efficient and showed no significant batch effect (Supple- – eases10 12. The dysregulation of other immune cell com- mentary Fig. S1c). Erythrocytes were not included in partments, such as monocytes, dendritic cells (DCs), and subsequent analysis and cycling cells were reclustered into innate-like T cells is also likely present in severe COVID- cycling T, cycling PC, and cycling NK cells based on – 1913 16. specific markers (Supplementary Fig. S1d, e). This dataset To unravel the barely known immune mechanisms indicated significantly dysregulated peripheral immune underlying COVID-19 pathogenesis in an unbiased and landscapes in COVID-19 patients compared to HC, comprehensive manner, we and others have applied the especially among severe cases (Fig. 1d). The most pro- single-cell RNA sequencing (scRNA-seq) to profile the minent changes included an expansion of monocyte and immune cell heterogeneity and dynamics in BALFs, blood, cycling T cells and a reduction of NK, T, and mDC and respiratory tract samples from the COVID-19 populations, thus resulting in largely increased monocyte/ patients. Collectively, those studies revealed a stunted T cell ratios in COVID-19 patients (Fig. 1e, f). The fre- IFN response, depletion of natural killer (NK) and T quency of pDCs was also decreased in severe COVID-19, lymphocytes, loss of major histocompatibility class although the difference was not statistically significant. (MHC) class II molecules, and significantly elevated levels Together, these data show that SARS-CoV-2 infection of chemokine production from monocytes in the greatly perturbs the blood immune cell compartments, – patients8,9,13,14,17 19. However, a complete picture of the particularly in those with severe diseases. COVID-19-induced immune perturbation has not been generated. Here we conducted scRNA-seq analysis of Remodeling of circulating myeloid cell populations in paired blood and BALF samples from the same COVID- patients with COVID-19 19 patients. Our data revealed profound alterations of We observed that the proportions of monocytes were various immune compartments and depicted a dichotomy increased in COVID-19 patients, especially in those with of peripheral immune paralysis and broncho-alveolar severe diseases. To further understand the remodeling of immune hyperactivation in COVID-19 patients. myeloid cell compartment, we re-clustered myeloid cells + and identified five distinct cell types including CD14 + + Results classic monocyte, CD14 CD16 intermediate monocytes, + The overview of dysregulated peripheral immune CD16 non-classic monocytes, DC1, and DC2 (Fig. 2a landscape in severe COVID-19 patients and Supplementary Fig. S2a). The composition of myeloid A high-quality scRNA-seq dataset composed of 200,059 cells in severe COVID-19 patients differed significantly cells were generated that characterized peripheral from that of mild cases and controls. Proportion of + immune cells from three healthy controls (HC), five mild, CD14 monocyte increased significantly in severe and eight severe COVID-19 patients (Fig. 1a). The COVID-19 compared to that in the mild COVID-19 and + metadata of these patients is listed in Supplementary control group, whereas those of CD16 non-classical + + Table S1. Patients with mild diseases were all cured and monocyte (vs controls), CD14 CD16 monocytes (vs discharged after 11–18 days of hospitalization, 2 of the 8 mild COVID-19), and DC2 significantly (vs mild COVID- patients with severe diseases succumbed, whereas other 19 and controls) decreased in severe COVID-19 severe cases recovered after 12–58 days of hospitalization. (Fig. 2b, c). + The clinical course of this patient cohort is similar to CD14 monocytes represent the major peripheral earlier reports, where elderly patients with underlying myeloid cell type, and differential Uniform Manifold diseases were prone to develop severe symptoms and Approximation and Projection (UMAP) projection pat-
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